Recent Expansions on Cellular Models to Uncover the Scientific Barriers Towards Drug Development for Alzheimer's Disease.

Globally, the central nervous system (CNS) disorders appear as the most critical pathological threat with no proper cure. Alzheimer's disease (AD) is one such condition frequently observed with the aged population and sometimes in youth too. Most of the research utilizes different animal models for in vivo study of AD pathophysiology and to investigate the potency of the newly developed therapy. These in vivo models undoubtably provide a powerful investigation tool to study human brain. Although, it sometime fails to mimic the exact environment and responses as the human brain owing to the distinctive genetic and anatomical features of human and rodent brain. In such condition, the in vitro cell model derived from patient specific cell or human cell lines can recapitulate the human brain environment. In addition, the frequent use of animals in research increases the cost of study and creates various ethical issues. Instead, the use of in vitro cellular models along with animal models can enhance the translational values of in vivo models and represent a better and effective mean to investigate the potency of therapeutics. This strategy also limits the excessive use of laboratory animal during the drug development process. Generally, the in vitro cell lines are cultured from AD rat brain endothelial cells, the rodent models, human astrocytes, human brain capillary endothelial cells, patient derived iPSCs (induced pluripotent stem cells) and also from the non-neuronal cells. During the literature review process, we observed that there are very few reviews available which describe the significance and characteristics of in vitro cell lines, for AD investigation. Thus, in the present review article, we have compiled the various in vitro cell lines used in AD investigation including HBMEC, BCECs, SHSY-5Y, hCMEC/D3, PC-2 cell line, bEND3 cells, HEK293, hNPCs, RBE4 cells, SK-N-MC, BMVECs, CALU-3, 7W CHO, iPSCs and cerebral organoids cell lines and different types of culture media such as SCM, EMEM, DMEM/F12, RPMI, EBM and 3D-cell culture.

Diverse cellular colonizing endophytic bacteria in field shoots and in vitro cultured papaya with physiological and functional implications.

The study was envisaged to assess the extent of normally uncultivable endophytic bacteria in field papaya plants and in vitro established cultures adopting cultivation vs molecular analysis and microscopy. Surface-sterilized axillary shoot-buds of papaya 'Arka Surya' revealed high bacterial diversity as per 16S rRNA metagene amplicon sequencing (6 phyla, 10 classes, 21 families) with an abundance of Pseudomonas (Gammaproteobacteria), which also formed a common contaminant for in vitro cultured field explants. Molecular analysis of seedling shoot-tip-derived healthy proliferating cultures of three genotypes ('Arka Surya', 'Arka Prabhath', 'Red Lady') with regular monthly subculturing also displayed high bacterial diversity (11-16 phyla, >25 classes, >50 families, >200 genera) about 12-18 months after initial establishment. 'Arka Surya' and 'Red Lady' cultures bore predominantly Actinobacteria (75-78%) while 'Arka Prabhath' showed largely Alphaproteobacteria corroborating the slowly activated Methylobacterium sp. Bright-field direct microscopy on tissue sections and tissue homogenate and epi-fluorescence microscopy employing bacterial DNA probe SYTO-9 revealed abundant intracellular bacteria embracing the next-generation sequencing elucidated high taxonomic diversity. Phylogenetic investigation of communities by reconstruction of unobserved states- PICRUSt- functional annotation suggested significant operational roles for the bacterial-biome. Metabolism, environmental information processing, and genetic information processing constituted major Kyoto Encyclopedia of Genes and Genomes KEGG attributes. Papaya stocks occasionally displayed bacterial growth on culture medium arising from the activation of originally uncultivable organisms to cultivation. The organisms included Bacillus (35%), Methylobacterium (15%), Pseudomonas (10%) and seven other genera (40%). This study reveals a hidden world of diverse and abundant conventionally uncultivable cellular-colonizing endophytic bacteria in field shoots and micropropagating papaya stocks with high genotypic similarity and silent participation in various plant processes/pathways.

Virtual Monochromatic Dual-Energy Aortoiliac CT Angiography With Reduced Iodine Dose: A Prospective Randomized Study.

OBJECTIVE: The purpose of this study was to assess the feasibility of performing abdominopelvic aortoiliac CT angiography (CTA) with 16.0 g of iodine contrast medium acquired with low-energy (40 and 50 keV) virtual monochromatic (VMC) images with rapid-kilovoltage-switching dual-energy CT. SUBJECTS AND METHODS: A total of 52 adults with abdominal aortoiliac aneurysm and prior 120-kVp single-energy CTA (SECTA) with 33 g iodine (standard dose) underwent follow-up dual-energy CTA (DECTA) with a 52% reduced iodine dose. Subjects were randomly assigned to a contrast medium protocol for DECTA examinations: one group (n = 26) received 16.2 g (270 mg I/mL) and the other (n = 26) received 16.0 g (320 mg I/mL). Two readers independently assessed SECTA and VMC DECTA datasets for image quality using a 5-point scale. Aortoiliac intravascular attenuation was measured, and ANOVA was used to compare measurements between VMC DECTA and SECTA images. In a subset of patients with DECTA after endovascular aortic repair, endoleak detection was evaluated on VMC images. Volume CT dose index, dose-length product, and size-specific dose estimate were compared between DECTA and SECTA. RESULTS: All DECTA examinations (n = 52) were rated diagnostic with image quality scores comparable to those of 120-kVp single-energy CTA (40 keV, 4.2-4.4; 50 keV, 4.6-4.8; SECTA, 4.4-4.5). Intravascular attenuation was uniform in all reduced-iodine DECTA examinations and was significantly higher on 40- and 50-keV images than on standard-iodine-dose SECTA images (720 ± 125 HU and 482 ± 82 HU vs 303 ± 65 HU) (p < 0.01). There was no difference in intravascular attenuation between the 16.2-g and the 16.0-g doses (p = 0.82). Sensitivity and specificity for endoleak detection were 78.9-94.7% and 100%. Total dose-length product was lower for DECTA (788 ± 166 mGy · cm) than for SECTA (1114 ± 468 mGy · cm). CONCLUSION: Low-energy VMC DECTA images (40 and 50 keV) acquired with two contrast protocols at approximately 50% reduced iodine dose (16.0 and 16.2 g) provide adequate intravascular attenuation and diagnostic quality for aortoiliac evaluation.

Use of Plant Preservative Mixture™ for establishing in vitro cultures from field plants: Experience with papaya reveals several PPM™ tolerant endophytic bacteria.

KEY MESSAGE: Prevalence of diverse PPM™-tolerant endophytic bacteria in papaya, the broad-spectrum microbicide specified for use in plant tissue cultures, capable of surviving covertly in MS-based medium, with implications in contamination management. Plant Preservative Mixture™ was employed for establishing papaya (Carica papaya) tissue cultures from field explants. Comparing three recommended practices for controlling endogenous microbial contaminants, axillary shoot tips (1.0-1.5 cm) from cv. Arka Prabhath were treated with PPM™ 5% for 4 h (T1), 50% for 10 min (T2) or 100% for 10 min (T3) and cultured in MS-based papaya establishment medium (PEM). By 4-6 weeks, all treatments proved non-rewarding with cultures succumbing either to microbial contamination (80% in T1) or phytotoxicity effect/contamination (90% in T2 and 95% in T3). Another trial adopting a multi-step surface sterilization treatment (carbendazim-cetrimide-HgCl2) followed by culturing in 0.05% PPM-supplemented PEM showed 35% obvious bacterial contamination compared with 40% in control. Single colonies from pooled bacterial growths were tested on 0.1% PPM-incorporated nutrient agar (NA) registering 60% isolates as PPM sensitive. Twenty PPM-surviving isolates were selected and identified. This showed 85% Gram-positive bacteria including 80% under phylum Firmicutes (55% spore-forming Bacillaceae and 25% Staphylococcaceae) and 5% Actinobacteria, and 15% Gram-negative Proteobacteria. About 50% isolates remained wholly non-obvious upon culturing on PEM while the rest showed slow growth with many displaying growth enhancement upon host tissue extract supplementation. Culturing the isolates on PPM-supplemented NA indicated 90-95% as tolerating 0.05-0.1% PPM and 65% overriding 0.2% PPM. The isolates, however, did not display obvious growth in PPM-supplemented PEM where the spore formers survived. The results indicate the prevalence of diverse PPM™-tolerant endophytic bacteria in papaya most of which survive covertly in MS-based medium and the need for taking this into account while using PPM™ for contamination management.

Prospective Comparison of Reduced-Iodine-Dose Virtual Monochromatic Imaging Dataset From Dual-Energy CT Angiography With Standard-Iodine-Dose Single-Energy CT Angiography for Abdominal Aortic Aneurysm.

OBJECTIVE: The purpose of this study was to compare the image quality of reduced-iodine-dose single-source dual-energy CT angiography (CTA) with that of standard-iodine-dose single-energy CTA in examinations of patients with abdominal aortic aneurysm and to assess the effect of the concentration of iodinated contrast medium on intravascular enhancement and image quality of reduced-iodine-dose CTA. SUBJECTS AND METHODS: In a prospective randomized clinical trial, 66 consecutively registered patients with abdominal aortic aneurysm who had previously undergone single-energy CTA (30-37 g I) underwent follow-up CTA at a reduced dose (21-27 g I) of iodinated contrast medium of either 270 mg I/mL (n = 33) or 320 mg I/mL (n = 33). Two readers independently evaluated virtual monochromatic imaging datasets (40-140 keV) and single-energy CTA images for image quality and noise and their preference for optimal energy virtual monochromatic imaging dataset. A value of p < 0.05 was considered statistically significant. RESULTS: All 66 dual-energy CTA examinations were rated diagnostic with mean image quality and image noise scores of 4.8 and 4.5 for reader 1 and 3.8 and 3.4 for reader 2 compared with single-energy CTA results of 4.5 and 4.2 for reader 1 and 4.5 and 4.1 for reader 2. Low-energy virtual monochromatic images (40-60 keV) from reduced-iodine-dose (28%) dual-energy CTA had significantly higher intravascular aortic attenuation (26-185%) and contrast-to-noise ratio (CNR) (20-25%) than standard-iodine-dose single-energy CTA images (p < 0.0001). No significant difference was found between patients who received 270 and those who received 320 mg I/mL with respect to intravascular aortic attenuation (p = 0.6331) or CNR (p = 0.9775). CONCLUSION: Low-energy virtual monochromatic imaging datasets from reduced-iodine (24 g I) single-source dual-energy CTA of the abdomen provide up to 185% higher attenuation and 25% higher CNR than standard-iodine-dose (33.3 g I) single-energy CTA while offering a wide range of energy settings irrespective of the concentration of IV contrast medium used.

Material Separation Using Dual-Energy CT: Current and Emerging Applications.

Dual-energy (DE) computed tomography (CT) offers the opportunity to generate material-specific images on the basis of the atomic number Z and the unique mass attenuation coefficient of a particular material at different x-ray energies. Material-specific images provide qualitative and quantitative information about tissue composition and contrast media distribution. The most significant contribution of DE CT-based material characterization comes from the capability to assess iodine distribution through the creation of an image that exclusively shows iodine. These iodine-specific images increase tissue contrast and amplify subtle differences in attenuation between normal and abnormal tissues, improving lesion detection and characterization in the abdomen. In addition, DE CT enables computational removal of iodine influence from a CT image, generating virtual noncontrast images. Several additional materials, including calcium, fat, and uric acid, can be separated, permitting imaging assessment of metabolic imbalances, elemental deficiencies, and abnormal deposition of materials within tissues. The ability to obtain material-specific images from a single, contrast-enhanced CT acquisition can complement the anatomic knowledge with functional information, and may be used to reduce the radiation dose by decreasing the number of phases in a multiphasic CT examination. DE CT also enables generation of energy-specific and virtual monochromatic images. Clinical applications of DE CT leverage both material-specific images and virtual monochromatic images to expand the current role of CT and overcome several limitations of single-energy CT. (©)RSNA, 2016.

Radiation Dose Consideration in Kidney Stone CT Examinations: Integration of Iterative Reconstruction Algorithms With Routine Clinical Practice.

OBJECTIVE: The objective of our study was to evaluate three commercially available iterative reconstruction (IR) algorithms-ASiR, iDOSE, and SAFIRE-and conventional filtered back projection (FBP) on image quality and radiation dose in kidney stone CT examinations. MATERIALS AND METHODS: During the 6-month study period, 684 unenhanced kidney stone CT examinations of consecutive adults were performed on 17 CT scanners (GE Healthcare [vendor 1], n = 12 scanners; Philips Healthcare [vendor 2], n = 2; Siemens Health-care [vendor 3], n = 3); these examinations were retrieved using dose-monitoring software (eXposure). A total of 347 kidney stone CT examinations were reconstructed using FBP, and 337 examinations were processed using IR (ASiR, n = 248; iDOSE, n = 50; SAFIRE, n = 39). The standard-dose scanning parameters for FBP scanners included a tube potential of 120 kVp, a tube current of 75-450 mA for vendor 1 and a Quality Reference mAs of 160-180 for vendor 3, and a slice thickness of 2.5 or 5 mm. The dose-modified protocol for the IR scanners included a higher noise index (1.4 times higher than the standard-dose FBP protocol) for vendor 1, a lower reference tube current-exposure time product for vendor 2 (150 reference mAs), and a lower Quality Reference mAs for vendor 3 (120 Quality Reference mAs). Three radiologists independently reviewed 60 randomly sampled kidney stone CT examinations for image quality, noise, and artifacts. Objective noise and attenuation were also determined. Size-specific dose estimates (SSDEs) were compared using ANOVA. RESULTS: Significantly higher subjective and objective measurements of image noise were found in FBP examinations compared with dose-modified IR examinations (p < 0.05). The radiation dose was substantially lower for the dose-modified IR examinations than the standard-dose FBP examinations (mean SSDE ± SD: 8.1 ± 3.8 vs 11.6 ± 3.6 mGy, respectively) (p < 0.0001), but the radiation dose was comparable among the three IR techniques (ASiR, 7.8 ± 3.1 mGy; iDOSE, 7.5 ± 1.9 mGy; SAFIRE, 7.6 ± 3.2 mGy) (p > 0.05). CONCLUSION: The three IRs enable 20-33% radiation dose reduction in kidney stone CT examinations compared with the FBP technique without any image quality concerns. The radiation dose and image quality were comparable among these three IR algorithms.

Autologous breast reconstruction: preoperative magnetic resonance angiography for perforator flap vessel mapping.

BACKGROUND: Selection of a vascular pedicle for autologous breast reconstruction is time consuming and depends on visual evaluation during the surgery. Preoperative imaging of donor site for mapping the perforator artery anatomy greatly improves the efficiency of perforator selection and significantly reduces the operative time. In this article, we present our experience with magnetic resonance angiography (MRA) for perforator vessel mapping including MRA technique and interpretation. METHODS: We have performed over 400 MRA examinations from August 2008 to August 2013 at our institution for preoperative imaging of donor site for mapping the perforator vessel anatomy. Using our optimized imaging protocol with blood pool magnetic resonance imaging contrast agents, multiple donor sites can be imaged in a single MRA examination. Following imaging using the postprocessing and reporting tool, we estimated incidence of commonly used perforators for autologous breast reconstruction. RESULTS: In our practice, anterior abdominal wall tissue is the most commonly used donor site for perforator flap breast reconstruction and deep inferior epigastric artery perforators are the most commonly used vascular pedicle. A thigh flap, based on the profunda femoral artery perforator has become the second most used flap at our institution. In addition, MRA imaging also showed evidence of metastatic disease in 4% of our patient subset. CONCLUSION: Our MRA technique allows the surgeons to confidently assess multiple donor sites for the best perforator and flap design. In conclusion, a well-performed MRA with specific postprocessing provides an accurate method for mapping perforator vessel, at the same time avoiding ionizing radiation.

Morphine three-dimensional T1 gadoxetate MR cholangiography of potential living related liver donors.

PURPOSE: To assess low-dose morphine for distension and improved visualization of intrahepatic bile ducts on T1 MR cholangiography (MRC) in preoperative imaging of potential liver donors. MATERIALS AND METHODS: Sixty-nine consecutive potential living related liver donors (mean age, 39 years; age range, 20 to 59 years) referred for pre-transplant MRI evaluation were evaluated without (n=30) or with (n=39) intravenous morphine injection (0.04 mg/kg). Morphine was injected pre-MRI while establishing intravenous access to allow ∼1 h for biliary distension before T1 MRC. Three radiologists reviewed intrahepatic biliary branch order visualization, common bile duct (CBD) diameter, and overall image quality. In 25 patients undergoing liver donation surgery, T1 MRC findings were correlated with intraoperative findings. This retrospective study was approved by the institutional review board. RESULTS: Biliary visualization was improved post-morphine administration with biliary duct branch order visualization score of 3.2 and 3.3 at 45 and 60 min, respectively, compared with 2.7 without morphine (P<0.002); CBD diameter measured 5.3 and 5.5 versus 4.1 mm (P<0.005), and overall image quality score was 2.4 and 2.6 versus 1.8 (P<0.0006). Operative notes confirmed T1 MRC findings in 6/11 donors without morphine and 14/14 donors with morphine. CONCLUSION: Intravenous low-dose morphine distends and improves visualization of bile ducts on T1 gadoxetate MRC.

New and evolving concepts in CT for abdominal vascular imaging.

Computed tomographic (CT) angiography has become the standard of care, supplanting invasive angiography for comprehensive initial evaluation of acute and chronic conditions affecting the vascular system in the abdomen and elsewhere. Over the past decade, the capabilities of CT have improved substantially; simultaneously, the expectations of the referring physician and vascular surgeons have also evolved. Increasingly, CT angiography is used as an imaging biomarker for treatment selection and assessment of effectiveness. However, the growing use of CT angiography has also introduced some challenges, as potential radiation-associated and contrast media-induced risks need to be addressed. These concerns can be partly confronted by modifying scanning parameters (applying a low tube voltage) with or without using software-based solutions. Most recently, multienergy technology has endowed CT with new capabilities offering improved CT angiographic image quality and novel plaque characterization while decreasing radiation and iodine dose. In this article, we discuss current and new approaches using both conventional and multienergy CT for studying vascular disease in the abdomen. We propose various approaches to overcoming commonly encountered image quality challenges in CT angiography. In addition, we describe supplemental strategies for improving patient safety that leverage the available technology.

Oncologic applications of dual-energy CT in the abdomen.

Dual-energy computed tomographic (DECT) technology offers enhanced capabilities that may benefit oncologic imaging in the abdomen. By using two different energies, dual-energy CT allows material decomposition on the basis of energy-dependent attenuation profiles of specific materials. Although image acquisition with dual-energy CT is similar to that with single-energy CT, comprehensive postprocessing is able to generate not only images that are similar to single-energy CT (SECT) images, but a variety of other images, such as virtual unenhanced (VUE), virtual monochromatic (VMC), and material-specific iodine images. An increase in the conspicuity of iodine on low-energy VMC images and material-specific iodine images may aid detection and characterization of tumors. Use of VMC images of a desired energy level (40-140 keV) improves lesion-to-background contrast and the quality of vascular imaging for preoperative planning. Material-specific iodine images enable differentiation of hypoattenuating tumors from hypo- or hyperattenuating cysts and facilitate detection of isoattenuating tumors, such as pancreatic masses and peritoneal disease, thereby defining tumor targets for imaging-guided therapy. Moreover, quantitative iodine mapping may serve as a surrogate biomarker for monitoring effects of the treatment. Dual-energy CT is an innovative imaging technique that enhances the capabilities of CT in evaluating oncology patients.

Unveiling the potential of photodynamic therapy with nanocarriers as a compelling therapeutic approach for skin cancer treatment: current explorations and insights.

Skin carcinoma is one of the most prevalent types of carcinomas. Due to high incidence of side effects in conventional therapies (radiotherapy and chemotherapy), photodynamic therapy (PDT) has gained huge attention as an alternate treatment strategy. PDT involves the administration of photosensitizers (PS) to carcinoma cells which produce reactive oxygen species (ROS) on irradiation by specific wavelengths of light that result in cancer cells' death via apoptosis, autophagy, or necrosis. Topical delivery of PS to the skin cancer cells at the required concentration is a challenge due to the compounds' innate physicochemical characteristics. Nanocarriers have been observed to improve skin permeability and enhance the therapeutic efficiency of PDT. Polymeric nanoparticles (NPs), metallic NPs, and lipid nanocarriers have been reported to carry PS successfully with minimal side effects and high effectiveness in both melanoma and non-melanoma skin cancers. Advanced carriers such as quantum dots, microneedles, and cubosomes have also been addressed with reported studies to show their scope of use in PDT-assisted skin cancer treatment. In this review, nanocarrier-aided PDT in skin cancer therapies has been discussed with clinical trials and patents. Additionally, novel nanocarriers that are being investigated in PDT are also covered with their future prospects in skin carcinoma treatment.

Fast 3D contrast enhanced MRI of the liver using temporal resolution acceleration with constrained evolution reconstruction.

Time-resolved imaging is crucial for the accurate diagnosis of liver lesions. Current contrast enhanced liver magnetic resonance imaging acquires a few phases in sequential breath-holds. The image quality is susceptible to bolus timing errors, which could result in missing the critical arterial phase. This impairs the detection of malignant tumors that are supplied primarily by the hepatic artery. In addition, the temporal resolution may be too low to reliably separate the arterial phase from the portal venous phase. In this study, a method called temporal resolution acceleration with constrained evolution reconstruction was developed with three-dimensional volume coverage and high-temporal frame rate. Data is acquired using a stack of spirals sampling trajectory combined with a golden ratio view order using an eight-channel coil array. Temporal frames are reconstructed from vastly undersampled data sets using a nonlinear inverse algorithm assuming that the temporal changes are small at short time intervals. Numerical and phantom experimental validation is presented. Preliminary in vivo results demonstrated high spatial resolution dynamic three-dimensional images of the whole liver with high frame rates, from which numerous subarterial phases could be easily identified retrospectively.

Improved hepatic arterial phase MRI with 3-second temporal resolution.

PURPOSE: To assess 3-s temporal resolution for arterial phase bolus timing on dynamic liver MRI. MATERIALS AND METHODS: One hundred consecutive patients undergoing fluoro-triggered dynamic gadoxetate enhanced liver MRI with standard Cartesian k-space LAVA (Liver Acquisition with Volume Acceleration) were compared with 61 consecutive patients imaged using spiral k-space LAVA reconstructed at 3-s temporal resolution with sliding window reconstruction. For qualitative analysis, bolus timing, hepatic artery branch order visualized, and overall image quality were evaluated. For quantitative analysis, contrast to noise ratio between aorta and liver parenchyma, aorta and portal vein, and signal intensity ratio between aorta and liver parenchyma were calculated. RESULTS: MR fluoroscopy triggered single phase standard LAVA produced optimal arterial phase timing in 35% patients, compared with 88% with Spiral LAVA (P < 0.0001). Spiral LAVA had superior bolus timing scoring 2.0, compared with 1.0 with standard LAVA (P < 0.0001). Overall image quality and hepatic artery branch order visualization scoring were superior on spiral LAVA, compared with standard LAVA (P < 0.001). The aorta to liver parenchyma signal intensity ratio was also superior on spiral LAVA, compared with standard LAVA (2.8 vs. 2.2; P < 0.001). CONCLUSION: Dynamic liver MRI bolus timing improves using 3-s temporal resolution.

In vitro-in vivo correlation in nanocarriers: From protein corona to therapeutic implications.

Understanding and establishing a link between the physicochemical characteristics of nanoparticles (NPs) and their biological interactions poses to be a great challenge in the field of nanotherapeutics. Recent analytical advancements concerning bio-nanointerfaces have accelerated the quest to comprehend the fate of nanocarrier systems in vivo. Scientists have discovered that protein corona, an adsorbed layer of biomolecules on the surface of NPs takes a leading part in interacting with cells and in the cellular uptake process, thereby determining the in vivo behaviour of NPs. Another useful method to assess the in vivo fate of NPs is by performing dissolution testing. This forms the basis for in vitro in vivo correlation (IVIVC), relating in vitro dissolution of NPs and their in vivo properties. Scientists are continuously directing their efforts towards establishing IVIVC for different nanocarrier systems while concurrently gaining insights into protein corona. This review primarily summarizes the importance of protein corona and its interaction with nanoparticles. It also gives an insight into the factors affecting the interaction and various in vitro dissolution media used for varied nanocarrier systems. The article concludes with a discussion of the limitations of IVIVC modelling and its position from a regulatory perspective.

Application of thermoresponsive smart polymers based in situ gel as a novel carrier for tumor targeting.

The temperature-triggered in situ gelling system has been revolutionized by introducing an intelligent polymeric system. Temperature-triggered polymer solutions are initially in a sol state and then undergo a phase transition to form a gel at body temperature due to various parameters like pH, temperature, and so on. These smart polymers offer a number of advantages, including ease of administration, long duration of release of the drug, low administration frequency with good patient compliance, and targeted drug delivery with fewer adverse effects. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm), polyethylene glycol (PEG), poly (N, N'-diethyl acrylamide), and polyoxypropylene (PPO) have been briefly discussed. In addition to various novel Drug Delivery Systems (DDS), the smart temperature-triggered polymeric system has various applications in cancer therapy and many other disease conditions. This review focuses on the principals involved in situ gelling systems using various temperature-triggered polymers for chemotherapeutic purposes, using smart DDS, and their advanced application in cancer therapy, as well as available marketed formulations and recent advances in these thermoresponsive sol-gel transforming systems.

Recent advancements on in vitro blood-brain barrier model: A reliable and efficient screening approach for preclinical and clinical investigation.

INTRODUCTION: The efficiency of brain therapeutics is greatly hindered by the blood-brain barrier (BBB). BBB's protective function, selective permeability, and dynamic functionality maintain the harmony between the brain and peripheral region. Thus, the design of any novel drug carrier system requires the complete study and investigation of BBB permeability, efflux transport, and the effect of associated cellular and non-vascular unit trafficking on BBB penetrability. The in vitro BBB models offer a most promising, and reliable mode of initial investigation of BBB permeability and associated factors as strong evidence for further preclinical and clinical investigation. AREA COVERED: This review work covers the structure and functions of BBB components and different types of in vitro BBB models along with factors affecting BBB model development and model selection criteria. EXPERT OPINION: In vivo models assume to reciprocate the physiological environment to the maximum extent. However, the interspecies variability, NVUs trafficking, dynamic behavior of BBB, etc., lead to non-reproducible results. The in vitro models are comparatively less complex, and flexible, as per the study design, could generate substantial evidence and help identify suitable in vivo animal model selection.

Nose-to-brain drug delivery for the treatment of Alzheimer's disease: current advancements and challenges.

INTRODUCTION: The irreversible destruction of neurons, progressive loss of memory and cognitive behavior, high cost of therapy, and impact on society, desire a better, effective, and affordable treatment of AD. The nose-to-brain delivery approach holds great potential to access the brain without any hindrance of BBB and results in higher bioavailability and thus better therapeutic efficacy of anti-AD drugs. AREAS COVERED: The present review article highlights the current facts and worldwide statistics of AD and its detailed etiology. This is followed by barriers to brain delivery, nose-to-brain delivery, their limitations, and amalgamation with various novel carrier systems. We have emphasized recent advancements in nose-to-brain delivery using mucoadhesive, stimuli-responsive carriers, polymeric nanoparticles, lipid nanoparticles, and protein/peptide delivery for treatment of AD. EXPERT OPINION: The available therapies are symptomatic and mitigate the symptoms of AD at the initial stages. In lieu of this, nose-to-brain delivery has the ability to overcome these limitations and increase drug bioavailability in the brain. Various novel strategies including stimuli-responsive systems, nanoparticles, etc. enhance the nasal permeation, protect the drug, and enhance its therapeutic potency. However, successful preclinical data do not assure the clinical success of the therapy, and hence exhaustive clinical investigations are needed to make the therapy available for patients.

Application of chitosan modified nanocarriers in breast cancer.

As per the WHO, every year around 2.1 million women are detected with breast cancer. It is one of the most invasive cancer in women and second most among all, contributing around 15% of death worldwide. The available anticancer therapies including chemo, radio, and hormone therapy are associated with a high load of reversible and irreversible adverse effects, limited therapeutic efficacy, and low chances of quality survival. To minimize the side effects, improving therapeutic potency and patient compliance promising targeted therapies are highly desirable. In this sequence, various nanocarriers and target modified systems have been explored by researchers throughout the world. Among these chitosan-based nanocarriers offers one of the most interesting, flexible, and biocompatible systems. The unique characteristics of chitosan like surface flexibility, biocompatibility, hydrophilicity, non-toxic and cost-effective behavior assist to overcome the inadequacy of existing therapy. The present review throws light on the successes, failures, and current status of chitosan modified novel techniques for tumor targeting of bioactives. It also emphasizes the molecular classification of breast cancer and current clinical development of novel therapies. The review compiles most relevant works of the past 10 years focusing on the application of chitosan-based nanocarrier against breast cancer.

Overcoming skin barriers through advanced transdermal drug delivery approaches.

Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e., compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc., emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc., can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro, ex vivo, and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc., and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS.